The long-range goal of the proposed project is to provide a centralized, freely available resource with comprehensive, well-annotated data and analysis tools that informs hypothesis development and interpretation of environmental health studies and promotes understanding about the etiologies of environmental diseases. Most human diseases involve interactions between genetic and environmental factors. The environment is implicated in many common conditions such as asthma, cancer, and diabetes; however, the etiology of these widespread diseases remains unclear. More than 85,000 chemicals are currently used in commerce, challenging elucidation about chemical mechanisms of action and prioritization of environmental research. Integration of critical data with novel analysis approaches is required to understand environment-disease associations and is essential for improving toxicity prediction, risk assessment, regulation and development of effective therapeutic interventions. We developed the freely available Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org) to address this need. CTD provides manually curated data describing cross-species chemical-gene interactions and chemical- and gene-disease relationships from the peer-reviewed literature and integrates this information with select external data sets (e.g., molecular pathways) and novel analysis tools. In this application we propose to: 1) comprehensively curate chemical- gene-disease interactions and expand the scope of phenotype curation to include cellular and diverse organism effects that will enable users to: a) identify biomarkers of environmentally influenced diseases and b) infer potential human health consequences from toxicological studies in model organisms and in vitro studies; and 2) design and implement new tools to facilitate development, analysis and interpretation of novel hypotheses focused on chemical-gene-disease interaction networks. This proposed project will leverage our cutting-edge software development, curation expertise and well-established, flexible infrastructure to facilitate increased understanding of critical environmental health issues in direct alignment with emerging research priorities.